1. Field of the Invention
This invention relates to the fields of pharmacology and cancer treatment. More specifically, this invention relates to the combination of anticancer drugs with a drug-enhancing agent administered by aerosol for the treatment of lung cancer in vivo.
2. Description of the Related Art
Lung cancer remains the leading cause of cancer-related deaths. Traditional systemic routes of drug delivery have yielded limited results because of the inability to provide effective concentrations at the sites of cancer without encountering dose-limiting toxicity. An aerosol route for immediate administration of various therapeutic agents to the lungs has been described (1-3). Inhalation of liposomal formulations of the lipophilic anticancer drug, 9-nitrocamptothecin (9NC), was found to be effective against human cancer xenografts and experimental pulmonary metastases in mice at the doses significantly lower than used by other routes of administration (2, 4). A phase I clinical trial in patients with pulmonary cancer with 9NC aerosol treatment indicated that this treatment is sufficiently well tolerated for further clinical evaluation (5).
Paclitaxel (PTX) is among the promising anticancer agents for lung cancer therapy; it is a lipophilic agent with a wide spectrum of anticancer activity including refractory lung cancer (6). Its use, however, may be limited by acquired resistance of tumor cells to the drug. Several mechanisms of resistance to taxanes have been reported. The paclitaxel molecule disrupts tubulin dynamics and can cause cell proliferation arrest at G2/M phase (18). Paclitaxel is used extensively for treatment of lung cancer and is effective as a single agent, but also it is effective in combination therapy with other anticancer drugs and radiation (19-21). The drug is administered intravenously in a clinical setting since its bioavailability is poor after oral administration. The drug is currently administered in a mixture of polyoxyethylated castor oil and ethanol (Diluent-12) exclusively by continuous intravenous infusion. Paclitaxel's use has been limited by hypersensitivity reactions to Diluent-12 (7). In clinical studies it was shown that the bioavailability of paclitaxel administered orally increased 9-fold with concurrent administration of cyclosporin (22).
Liposomes were found to improve pharmacological characteristics of paclitaxel and to be less toxic compared to Diluent-12 (8, 9). Inhalation of liposomal formulation of paclitaxel by mice bearing renal carcinoma pulmonary metastases caused significant tumor growth inhibition and prolonged survival of the animals (2). In these experiments, the total inhaled deposited dose of paclitaxel was 6.3 mg/kg, administered 3 times/week. Dose-limiting toxicity was one of the reasons that prevented optimum use of the drug. Another reason could be the possible development of drug resistance by cancer cells.
The main mechanism of paclitaxel-induced resistance is associated with overexpression of plasma membrane glycoprotein (P-glycoprotein) which works as a drug transport protein that decreases intracellular drug concentrations. P-glycoprotein antagonists, including cyclosporins, are being investigated for use in combination with chemotherapeutic agents to enhance the apoptotic effect and to prevent resistance at the target site. In patients with established resistance remissions were observed when cyclosporin A or other cyclosporin was added to therapy, even when with the anticancer drug cytotoxin, the dose was reduced by as much as 3-fold (23).
Cyclosporin A has been successfully used to reverse the resistance of neoplastic cells to paclitaxel in vitro and in vivo (10, 11). However, one limiting factor is that cyclosporin A is a powerful immunosuppressive agent and can cause nephrotoxicity (30). Liposome formulation of cyclosporin A for inhalation have been developed and tested for the treatment of immunologically mediated lung diseases (3). Inhalation of cyclosporin A with the initial concentration of the drug in the nebulizer at 5 mg/ml during 30-45 min of inhalation was demonstrated to be safe for humans and rodents (3, 31).
Cyclosporins have a high-affinity binding capacity with P-glycoprotein. Competing with other drugs (taxanes, anthracyclines, epipodophyllotoxins, etc.) for binding with P-glycoprotein, cyclosporin A may prevent the active extrusion of these cytotoxic drugs from tumor cells (24, 25). Cyclosporin A is also known as an inhibitor of cytochrome P450-mediated (CYP) metabolism thereby inhibiting cytochrome P450-mediated first pass metabolism of paclitaxel (26). The main enzymes, CYP2C8 and CYP3C4, involved in paclitaxel metabolism belong to the P450 family and are expressed in the respiratory tissues (12, 13). These isoenzymes metabolize paclitaxel to 6α-hydroxypaclitaxel and 3ρ-hydroxypaclitaxel, respectively (12, 27).
P-glycoprotein and other resistance-associated proteins are expressed in normal human pulmonary tissue (28). In one study more than 60% of patients with non-small cell lung carcinoma were found to be positive for P-glycoprotein and 5-year survival rate of P-glycoprotein positive patients was significantly lower compared with those without P-glycoprotein (29). Moreover, the expression of the CYP3A4 gene was induced by administration of paclitaxel in lung cancer patients and the level of CYP2C expression in samples of lung cancer was significantly higher than in the normal lung tissue (13).
The prior art is deficient in the lack of a method of inhibiting the growth of pulmonary tumors. More specifically, the prior art lacks methods for the chemotherapeutic treatment of lung cancer in vivo via aerosol administration of anticancer drugs with cyclosporin A. The present invention fulfills this longstanding need and desire in the art.